Implications of finding synergic in vitro drug-drug interactions between interferon-α and ribavirin for the treatment of hepatitis C virus

Hepatitis C virus (HCV) infections are currently treated using a combination of interferon-alpha (IFN-alpha) and ribavirin (RBV). If IFN-alpha is utilized alone, the sustained virological response (SVR) rate is similar to20%, whereas when RBV is used alone it does not lead to an SVR. However, when IFN-alpha and RBV are used together, the combination leads to an SVR rate of similar to40%. This clinical synergy is thought to be due to the direct antiviral effects of RBV, or to indirect effects of RBV that stimulate the immune response. Evidence for either hypothesis is limited. Recently, we undertook an in vitro drug-drug combination analysis using surrogate model systems of HCV replication and found a reproducible synergy of antiviral effects between the two drugs at physiologically relevant drug concentrations. Our findings provide experimental support for the contention that the direct effects of these drugs' antiviral activity are responsible for the clinical synergy observed in patients.